This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Purpose: To assess the effect of PD-1 blockade on T cell dynamics and function, immune activation and viral replication in SIV-infected rhesus macaques in stable plateau phase. Hypothesis: Blocking the cellular activation inhibitory pathways PD-1/PD-L1 in vivo will enhance T cell activation, proliferation, and function resulting in better control of viremia and improved overall T cell function and homeostasis without significant triggering of unbalanced immune activation. Rational and Significance: PD-1 is upregulated on HIV-specific T cells, and expression levels are significantly correlated with both viral load and the reduced capacity of cytokine production and proliferation of HIV-specific CD8 T cells. Blocking the PD-1/PD-L1 pathway in vitro enhanced the capacity of HIV-specific CD8 T cells to proliferate and led to an increased cytokine and cytotoxic molecules production in response to cognate Ags. We have also recently reported that PD-1 level of expression correlates with the level of functionality of SIV-specific T cells. Moreover, our preliminary results indicated that PD-1 level of expression was also upregulated on memory compared to na[unreadable]ve B cells following viral infections. In addition, human anti-PD-L1 antibody (Medarex, MDX-1105), shown to enhance T cells activation and proliferation, was recently approved for Phase 1 clinical trial involving patients with advanced or recurrent solid tumors. Based on these findings, we hypothesized that in vivo blocking of PD-1/PD-L1 interaction would significantly enhance the activity, function, and proliferation of SIV-specific T cells. Of note, treating mice with anti-PD-1 was proven to be tolerated (safe) and did not induce toxic immune activations. This approach is expected to boost immunity against SIV/HIV chronic infection and would, hence, have a profound impact on treatment/vaccination against these viruses. Progress: As of this writing, we have treated two SIV-infected RM with the humanized anti-PD-1 mAb. We saw a dramatic up-regulation of memory T cell proliferation and transient expansion of memory T cell counts in blood. T cell responsiveness to superAg was also significantly enhanced at day 14 post treatment initiation. These studies are being extended to 4 additional SIV-infected RM in the next 8 weeks.